tert-butyl (+/-)-6-[(trans-1'-benzyl-4'-hydroxypyrrolidin-3'-yl)methyl]pyridin-2-ylcarbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl (+/-)-6-[(trans-1'-benzyl-4'-hydroxypyrrolidin-3'-yl)methyl]pyridin-2-ylcarbamate
• 英文别名: trans-[6-(1-benzyl-4-hydroxy-pyrrolidin-3-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester；[6-(1-benzyl-4-hydroxy-pyrrolidin-3-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester；tert-butyl N-[6-[[(3R,4S)-1-benzyl-4-hydroxypyrrolidin-3-yl]methyl]pyridin-2-yl]carbamate
• 化学式: C₂₂H₂₉N₃O₃
• 分子量: 383.491
• InChiKey: GPOMYIAVNNBSLG-IEBWSBKVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  74.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl (+/-)-6-[(trans-1'-benzyl-4'-hydroxypyrrolidin-3'-yl)methyl]pyridin-2-ylcarbamate 在 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以87%的产率得到tert-butyl (+/-)-6-[(1'-benzyl-4'-oxopyrrolidin-3'-yl)methyl]pyridin-2-ylcarbamate
  参考文献：
  名称：

  WO2008/42353

  摘要：

  公开号：
• 作为产物：
  描述：

  3-苄基-6-氧杂-3-氮杂双环[3.1.0]己烷 在 正丁基锂 作用下， 以 四氢呋喃 、 hexanes 为溶剂， 反应 6.0h， 以90%的产率得到tert-butyl (+/-)-6-[(trans-1'-benzyl-4'-hydroxypyrrolidin-3'-yl)methyl]pyridin-2-ylcarbamate
  参考文献：
  名称：

  [EN] HETEROAROMATIC SELECTIVE INHIBITORS OF NEURONAL NITRIC OXIDE SYNTHASE
  [FR] INHIBITEURS HETEROMATIQUES SELECTIFS D'OXYDE NITRIQUE SYNTHASE NEURONALE

  摘要：

  公开号：

  WO2005026111A3

文献信息

• Potent and highly selective heteroaromatic inhibitors of neuronal nitric oxide synthase
  申请人：Silverman B. Richard

  公开号：US20080108814A1

  公开（公告）日：2008-05-08

  Peptidomimetic compounds as can inhibit neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as but not limited to stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease.

  肽类类似物化合物可抑制神经元一氧化氮合酶(nNOS)，用于潜在的治疗神经退行性疾病，如中风、阿尔茨海默病、帕金森病、亨廷顿病等。
• Heteroaromatic Selective Inhibitors of Neuronal Nitric Oxide Synthase
  申请人：Silverman Richard B.

  公开号：US20090104677A1

  公开（公告）日：2009-04-23

  Compounds inhibiting neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, such compounds of a formula.

  抑制神经元一氧化氮合酶(nNOS)的化合物，用于潜在治疗神经退行性疾病，如中风、阿尔茨海默病、帕金森病、亨廷顿病等，这些化合物的公式为：
• Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives
  作者：Haitao Ji、Silvia L. Delker、Huiying Li、Pavel Martásek、Linda J. Roman、Thomas L. Poulos、Richard B. Silverman

  DOI：10.1021/jm100947x

  日期：2010.11.11

  Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((+/-)-32 and (+/-)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2 ''-(3 ''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2 ''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437-5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.
• Minimal Pharmacophoric Elements and Fragment Hopping, an Approach Directed at Molecular Diversity and Isozyme Selectivity. Design of Selective Neuronal Nitric Oxide Synthase Inhibitors
  作者：Haitao Ji、Benjamin Z. Stanton、Jotaro Igarashi、Huiying Li、Pavel Martásek、Linda J. Roman、Thomas L. Poulos、Richard B. Silverman

  DOI：10.1021/ja0772041

  日期：2008.3.1

  Fragment hopping, a new fragment-based approach for de novo inhibitor design focusing on ligand diversity and isozyme selectivity, is described. The core of this approach is the derivation of the minimal pharmacophoric element for each pharmacophore. Sites for both ligand binding and isozyme selectivity are considered in deriving the minimal pharmacophoric elements. Five general-purpose libraries are established: the basic fragment library, the bioisostere library, the rules for metabolic stability, the toxicophore library, and the side chain library. These libraries are employed to generate focused fragment libraries to match the minimal pharmacophoric elements for each pharmacophore and then to link the fragment to the desired molecule. This method was successfully applied to neuronal nitric oxide synthase (nNOS), which is implicated in stroke and neurodegenerative diseases. Starting with the nitroarginine-containing dipeptide inhibitors we developed previously, a small organic molecule with a totally different chemical structure was designed, which showed nanomolar nNOS inhibitory potency and more than 1000-fold nNOS selectivity. The crystallographic analysis confirms that the small organic molecule with a constrained conformation can exactly mimic the mode of action of the dipeptide nNOS inhibitors. Therefore, a new peptidomimetic strategy, referred to as fragment hopping, which creates small organic molecules that mimic the biological function of peptides by a pharmacophore-driven strategy for fragment-based de novo design, has been established as a new type of fragment-based inhibitor design. As an open system, the newly established approach efficiently incorporates the concept of early "ADME/Tox" considerations and provides a basic platform for medicinal Chemistry-driven efforts.
• US7470790B2
  申请人：——

  公开号：US7470790B2

  公开（公告）日：2008-12-30